Severe adverse reactions to meglumine antimoniate in the treatment of visceral leishmaniasis: a report of 13 cases in the southwestern region of Brazil

Introduction

Visceral leishmaniasis (VL) is considered to have been neglected by the mainstream pharmaceutical industry, due to the poor socioeconomic conditions of those affected by it. As a consequence, antimony-based medications continue to be the drugs of choice for the treatment of this pathology in the majority of countries, except for Bihar, India, where the resistance to these compounds has reached the alarming level of 60%. ¹

Meglumine antimoniate is used for treatment of LV in Brazil. Even though highly effective, pentavalent antimony derivatives have several adverse effects. Major known reactions (fever, chills, myalgia, arthralgia, cough, cutaneous eruptions and headache) are signs of intolerance, usually dose-independent and of early onset, ² indicative of immediate hypersensitivity and although bothersome, usually do not justify therapy discontinuation. Signs of intoxication (cardiac, hepatic, renal and haematologic toxicity) occur by the end of treatment, most often in the third week of drug use, and are indicative of a cumulative effect. ² The presence of pancreatitis in the setting of antimonial therapy was demonstrated after the recognition of cardiac, hepatic and haematological abnormalities, but the mechanism by which this collateral effect happens is not well understood. ³

In most cases, adverse reactions are transient and of low severity; nevertheless, some can be severe, requiring early recognition and proper management, which can include the temporary or permanent withdrawal of medication.

In the state of Mato Grosso do Sul, southwestern Brazil, a clear expansion of VL has occurred since 2000. Severe or even fatal adverse reactions to meglumine antimoniate were detected in some of the 107 patients treated at the teaching hospital of the Federal University of Mato Grosso do Sul (UFMS) in the capital Campo Grande from January 2004 to December 2005. The purpose of the present investigation was to study the cases of patients who suffered adverse reactions while being treated with meglumine antimoniate.

Patients and methods

The medical records of 107 patients (43 adults and 64 children) who were treated at UFMS from January 2004 to December 2005, and who used meglumine antimoniate, were reviewed. The clinical and laboratory data of patients who developed severe adverse reactions were analysed. Chi-square test for trend was used to compare the proportions. The statistical significance was defined as P ≤ 0.05. The study was approved by UFMS's Ethics Committee on Research on Human Subjects.

Results

Thirteen patients (12.1 %) developed severe adverse reactions to meglumine antimoniate (Glucantime^®, Aventis, Paris, France: Table 1). The dose employed was 20 mg Sb^v/kg/day, maximum three vials, except for one patient (No. 11), who received the medication twice in less than 24 hours (40 mg/kg/day). Minor side effects were not studied.

Adverse reactions occurred mostly in those 50 years or older (4/13, or 30.7%); the likelihood of adverse reactions increased with patient age (P < 0.001).

Predominant severe adverse reactions were renal failure (eight episodes, 61.5 %), pancreatitis (six episodes, 46.1%) and hepatic failure/hepatitis (five episodes, 38.4%). Congestive heart failure due to myocardiopathy was detected in two instances, and cardiac arrhythmia which led to death was seen in another.

The majority of the effects occurred within the first 10 days of therapy (nine cases, 69.2%), and were mainly acute renal failure and pancreatitis. Of the patients with pancreatitis, some showed increases in pancreatic enzymes in periods of time as short as four days after beginning treatment; one patient was immunosuppressed (HIV-infected). Cardiac toxicity occurred in the third week.

Of the eight patients who exhibited acute renal failure, five had abnormal (≥ 1.2 mg/dL) or in the upper limit (1.2 mg/dL) levels of creatinine at admission. Six of the 13 patients with severe reactions died (46.1%). All showed adverse effects which began two to 10 days after beginning therapy. Acute renal failure was present in all of them; hepatic compromise was detected in four and pancreatitis in one.

Discussion

Although the majority of the participants were children, severe adverse reactions were more frequently seen in adult patients. Indeed, the children tolerated the antimonials better than the adults.

Severe adverse effects of antimonials more often occur at the end of treatment because of the cumulative effect of these drugs. However, our study detected that in the majority, the reactions occurred early on in the course of therapy, mainly as acute renal failure and pancreatitis. Therefore it may be that there are other reasons for the toxicity.

Renal failure was one of the main early adverse effects, generally seen in the elderly with renal impairment before treatment. This probably was the factor that triggered the precocious toxicity of the drug. Elderly patients with previously deteriorated renal functions and acute renal failure have been reported by other authors. ² Renal function should be more closely monitored from the beginning of treatment.

Pancreatitis was another side effect that was manifested early on in the treatment. Gasser et al. ³ detected that, besides the pattern of a slow, progressive increase in serum amylase and lipase levels, patients may present abrupt, severe rises in their pancreatic enzymes after two or three doses of pentavalent antimony.

The elevation of pancreatic enzymes during treatment is common but usually asymptomatic. ³ Although four of our six patients with pancreatitis have been cured, the highly elevated pancreatic enzymes in the nine who died, and deaths reported in other studies, ⁴ shows that Sb^v-induced pancreatitis should not be considered as invariably benign and may be a serious, even fatal complication. Rises over four times the upper limit of amylase levels or 15 times the upper limit of lipase indicate drug discontinuation. ³

Severe liver involvement during treatment with antimonials is uncommon but was the second most frequent reaction in our patients who progressed to the death. The suspicion of a fatal hepatitis justifies the interruption of treatment if the level of one of the serum aminotransferases reaches five times the upper normal limit. ⁵

Cardiotoxicity is a frequently reported adverse reaction which develops slowly, particularly after the second week. It is demonstrated as repolarization changes in the electrocardiogram that do not have haemodynamic effects on the majority of cases but can sometimes lead to potentially fatal arrhythmias, ⁵ as in our patient No. 10. Careful monitoring of cardiac effects may detect the early signs of cardiotoxicity (prolongation of the corrected QT interval > 0.50 s, or T-wave flattening), thus indicating the discontinuation of treatment. For elderly, obese and those with underlying cardiac, hepatic or renal disease, twice-weekly or even more frequent monitoring may be indicated from the start of therapy. ⁵

Myocardiopathy followed by congestive heart failure, as presented by patients No. 2 and 3 is not a common adverse effect attributed to antimony. However, in India, six cases of severe heart failure were reported, with three deaths directly related to drug toxicity. ⁶

The cases investigated in our study suggest that antimonials can cause severe reactions, which can lead to death if not promptly identified. Contrary to what is generally expected, severe reactions can occur soon after starting treatment. Renal, hepatic, pancreatic and cardiac function must be carefully monitored, whether patients are hospitalized or attending outpatient therapy. A more careful assessment of the side effects is needed, mainly in adults and particularly in elderly patients with a previous deterioration of renal function. Our findings also warrant further study focusing on less toxic drugs, for improved treatment of patients with VL.